Zongertinib

Strong CYP3A Inducers : Avoid concomitant use with strong CYP3A inducers. If concomitant use cannot be avoided, increase HERNEXEOS dose. ( 7.1 ) BCRP Substrates : Avoid concomitant use with certain BCRP substrates where minimal concentration increase may lead to serious adverse reactions and consider alternative therapies. If concomitant use cannot be avoided, monitor patients closely for adverse reactions and follow recommendations provided in the BCRP substrate approved product labeling. For other BCRP substrates, monitor for increased adverse reactions and adjust the dosages of those substrates as clinically appropriate. ( 7.2 )

7.1 Effects of Other Drugs on HERNEXEOS Avoid concomitant use of HERNEXEOS with strong CYP3A inducers. If concomitant use cannot be avoided, increase HERNEXEOS dose as recommended [see Dosage and Administration (2.4) ]. Zongertinib is a CYP3A substrate. Strong CYP3A inducers decrease zongertinib exposure [see Clinical Pharmacology (12.3) ] , which may reduce effectiveness of HERNEXEOS.

7.2 Effects of HERNEXEOS on Other Drugs BCRP Substrates Avoid concomitant use of HERNEXEOS with certain BCRP substrates where minimal concentration changes may lead to serious adverse reactions. If coadministration cannot be avoided, monitor for increased adverse reactions and follow recommendations provided in the approved product labeling for the BCRP substrate. For other BCRP substrates, monitor for increased adverse reactions and adjust the dosages of those substrates as clinically appropriate. Zongertinib is a BCRP inhibitor. HERNEXEOS increases exposure of BCRP substrates [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates.

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ], HERNEXEOS can cause fetal harm when administered to a pregnant woman. There are no available data on the use of HERNEXEOS in pregnant women to inform a drug-associated risk. Oral administration of zongertinib to pregnant rats during the period of organogenesis caused structural abnormalities and alterations to growth at maternal exposures ≥ 19 times the human exposure based on AUC at the recommended dose [see Data ] . Advise pregnant women and females of reproductive potential of the potential risk to a fetus. In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study, pregnant rats received oral doses of 10, 30, or 60 mg/kg/day of zongertinib during the period of organogenesis (gestation day 7 to 18). Zongertinib caused decreased fetal weights, delayed development of the urinary system, and kidney hydronephrosis at 60 mg/kg/day (approximately 19 times the human exposure based on AUC at the recommended dose).

In an embryo-fetal development study in rabbits, there were no adverse embryo-fetal findings in pregnant animals administered oral doses of zongertinib up to 120 mg/kg/day (2.4 times the human exposure based on AUC at the recommended dose) during the period of organogenesis (gestation day 6 to 19). A literature-based assessment of the effects on reproduction demonstrated that mice expressing catalytically inactive HER2 die at mid-gestation due to cardiac dysfunction.